1. Field of the Invention
The present invention relates to a compound (formula XII, brivaracetam) and a method for preparing formula XII, which is a new generation of antiepileptic drug found by screening for ligands with a higher affinity for LBS than levetiracetam. LBS is a unique brain-specific Levetiracetam (LEV) binding site that is correlated with anticonvulsant effects in animal models of epilepsy.

2. Description of the Related Art
Epilepsy is one of the most common neurological disorders, affecting about 1 of the population worldwide. With currently available antiepileptic drugs (AEDs), one-third of patients continue to suffer from seizures even when treated at maximally tolerated dosages, either in monotherapy or in various drug combinations. Pharmacoresistance is associated with physical risks, reduced life expectancy, reduced quality of life and impairments in social opportunities. The acetamide derivate Levetiracetam (LEV) that primarily targets the synaptic vesicle protein 2A has been one of the most successful second-generation antiepileptic drugs. But irritability and other psychiatric adverse effects, such as depression, anger, and even psychosis, have been a “handicap” with Levetiracetam.
Brivaracetam is a Levetiracetam analog. Brivaracetam has an advantage over Levetiracetam in that it gets into the brain “much more quickly,” which means that “it could be used for status epilepticus, or acute seizures that cluster, or prolonged seizures”. From the Phase III trials, the self-reported rate of irritability with Brivaracetam was 2% for both drug doses (100 mg and 200 mg) vs 1% for placebo, which compares to as much as 10% for levetiracetam in some postmarketing studies.
With the improved safety profile and possibility to be used for wider range of epilepsy, Brivaracetam is considered as one of the most promising 3rd-generation anti-epileptic drugs.
Typically, a diastereomeric mixture of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]-butanamide and (2S)-2-[(4S)-2-oxo-4-propylpyrrolidin-1-yl]-butanamide (Brivaracetam) is synthesized and it is purified by chiral HPLC (U.S. Pat. Nos. 6,784,197, 7,629,474) (Scheme 1-1)—resulting in the problem of low yield.

U.S. Pat. No. 8,957,226 (Example 1, 3) and U.S. Pat. No. 8,338,621 (Example 4, 11), disclosed two routes to synthesize brivaracetam, which also have the same problem (Scheme 1-2).

The problem is the same in the process disclosed by the report of Kenda et al. (Journal of Medicinal Chemistry, 2004, 47, 530) (Scheme 1-3).

Technical Problem: To date, there is no enantioselective synthesis of brivaracetam. No scalable synthesis of enantiomerically pure brivaracetam without chiral column chromatography purification. The current processes to brivaracetam require tedious purification, significant loss of material, and high equipment investment.
There is a need to develop a cost effective method for the preparation of brivaracetam without chiral HPLC separation. The new preparation method should be applicable to the large-scale synthesis.